During the past several years, we have shown that the coactivator PGC-1 can activate and coordinate several key aspects of energy and glucose metabolism. It does this by binding to and coactivating a large number of nuclear receptors such as PPARgamma, HNF-4alpha, GR and other tissue-selective transcription factors such as MEF2C and NRF-1. Our emphasis in the next 5 years will be to determine in detail the physiological role of PGC-1 and key mechanisms that are used to activate its transcriptional properties. Our first Aim will be to determine with "state of the art" precision how PGC-1 alters respiration, mitochondrial uncoupling and the control of reactive oxygen species (ROS). Our second Aim will utilize "knock-out" mice (general and tissue-specific) for PGC-1 to determine the precise role of this protein in several processes where a function has been suggested - mitochondrial biogenesis, thermogenesis and glucose homeostasis. Physiological studies will utilize clamp technique to determine functions of specific tissues. Aim 3 investigates the molecular mechanisms whereby p38 MAP kinase can regulate both the degradation of PGC-1 and its transcriptional activity. In particular we will investigate whether and how p38 can modulate the ability of the APC ubiquitin ligase to interact with PGC-1. In a related Aim (4), we will use knock-out mice to investigate the rote of PGC-1 in the cachexia and hypermetabolism brought about in physiological states associated with elevated cytokines and p38 activation: infection and cancer. The last Aim (5) will begin studies of the biological role of a new, close homolog of PGC-1 we have termed PGC-1-beta. We will investigate the activities of this protein, which is expressed at very high levels in BAT and heart, on mitochondrial biogenesis, respiration and the determination of brown adiopytes. Disorders of energy balance and glucose homeostasis are key componenets of obesity and Type 2 diabetes, the most common metabolic disorders in the industrial world. These studies should elucidate key regulatory steps that may lead to new targeted therapies.